3-hydrazino-pyridazine-6-carboxamide



July 3, 1962 D. LIBERMAN 3,042,673

3-HYDRAZINO-PYRIDAZINE-G-CARBOXAMIDE Filed July 9, 1959 N NH (d) if 3/202 (YI) Hom-g ,co H20 N NH (e) YROH (W1) RUGCFCO H20 (m) R00 c--Z N INNH3 3,042,673 3-HYDPAZmPYhDAZllJE-6COXAMDE David Liber-man, Paris,France, assiguor to Chimie et Atomistique, Paris, France, a `French bodyFiled July 9, 1959, Ser. No. 826,025 Claims priority, application FranceJuly 26, 1958 1 Claim. (Cl. 261B-250) The object of the presentinvention is to provide a new pyridazine derivative:3-hydraZino-pyridazine-6carboxamide (compound I having the formula shownin FIG. l of the accompanying drawing) and the salts thereof formed withacids.

This compound, Whose melting point is 249-250 C., is an interestingintermediate agent in the synthetic preparation of new `activecompounds. Moreover, it possesses in itself marked hypotensiveproperties which make it a valuable therapeutic agent.

Another object of the invention is to provide a process of preparing3Lhydrazino-pyridazine--carboxamide, This process comprises reactinghydrazine with a 3-halogenopyridazine--carboxamide.

This reaction is illustrated by the stage h shown in FIG. 2 of theaccompanying drawing, the S-halogenopyridazine--carboxamide being thecompound IX in which Z represents a halogen and preferably chlorine.

The hydrazine is used in the form of hydrazine hydrate and the reactionis eiected by reiluxing the reactants in an anhydrous solvent, such asethyl alcohol.

The compound IX, which serves as the starting material, could itself beprepared from S-pyridazone-Gfcarboxylic acid as a result of thefollowing reactions, which is illustrated by the stages (e), (f), (g)shown in FIG. 2:

(l) Esteriication of 3-pyridazone6carboxylic acid (VI) by an ROHalcohol, R being a hydrocarbon radical which is preferably a lower`alkyl radical such as ethyl.

(2) Halogenation of the ester (VII) obtained by a halogenation agent Z2,such as for example phosphorus oxychloride, `thus obtaining -a3-halogeno-pyridazine-6- carboxylate (VIII).

(3) Treatment of Compound VIH by ammonia, giving the compound IX.

The synthetic preparation of 3hydrazinopyridazine6 carboxamide could be,moreover, more complete; the compound VI could be itself preparedsynthetically from simpler bodies. The stages (a) to (b) shown in FIG, 2illustrate this synthetic preparation, which is carried out in thefollowing way. Levulenic acid (II) is condensedV with hydrazine, whichprovides 6-methyl-pyridazinone (III), the pyridazinone obtained ishalogenated into 6-methyl 4 halogeno-3-pyridazinone (compound IV, whereZ represents a halogen and preferably bromine). Thehalogeno-pyridazinone is dehydrohalogenated by means of an alkali MOHinto 6-methyl-3-pyridazone (V), and the latter is oxidized so as toconvert the -methyl group into a carboxylic group.

The rsynthetic: preparation of 3-hydrazino-pyridazine-6- carboxamidefrom levulenic acid will be illustrated in more detail by the followingexample, to which the scope of the invention is in no Way limited.

EXAMPLE (a) -Methyl--Pyridnzinone (III) 500 g. of `approxiniately 98%hydrazine hydrate are added in small amounts to 1 kg. of levulenic acid.The mixture is cooled and filtered after several hours, and then driedunder a vacuum for about ten hours. Yield 846 g, (86%). M.P.=105 C.

(b) 6-Methyl4-Bromo3-Pyridaznone (IV) 400 g. of 6-methyl-pyridazinoneare dissolved in 1 litre 3,042,673 Patented July 3, 1962 (c)-MethyZ-S-Pyrz'dazone (V) A suspension of 575 g, of the bromiua-tedderivative is maintained in 1200 cc. of water in a water bath, and asolution of 200 g. of potassium hydroxide in y300 cc. of water is addedlittle by little. The pH is adjusted -to 7 by ladding the necessaryamount of KOH in tablet form. The heating is continued until completedissolution.

The mixture is `evaporated until dry in a water bath and the residue isextracted with ethyl acetate.

315 g. of hydrated product are obtained, having a M.P.=124-125 C. Thisproduct is dried under a vacuum for several hours at -100" C. Theanhydrous product melts at 14S-147 C. Yield 70%.

(d) 3-Pyrz'daz0ne-6-Carboxylic Acid (VI) In a three-necked ten litre askthere are dissolved, While agitating and cooling, 200 g. of-methyl-S-pyridazone in 2 litres of concentrated sulphuric acid.

There are then added, in small amounts and while agiytatiug, 536 g. ofcrushed potassium bichromate. When the temperature reaches 35-40 C., themixture is cooled with .iced water and maintained below 40 C. Themixture is agitated 6-7 hours, left over-night and then slowly pouredonto 7 kg. of crushed ice. It is ltered after 2 hours, Washed Vwithsmall yamounts of iced Water until the product is White, and then withalcohol and with ether and dried.

Yield: 190 g. (75%) of White powder. 257 C (dee).

150 ycc. of 20% hydrochloric alcohol. If everything does not dissolve, alittle more hydrochloric alcohol is added.

' The mixture is left to cool over-night and then ltered.

Yield: g. (72%) of ester. M.P.=l29130 C.

(f) Ethyl 3-Chloro-Pyrdazine--Carboxylate (VIII) 150 g. of ethyl3-pyridazone carboxylate are dissolved at C. in 1000 cc. of POC13. Themixture is refluxed for 30 minutes, `allowed to cool at 70 C. anddistilled under a vacuum of' l5 to 20 mm. of Hg, The cooled residue isremoved Ifrom the flask in several stages by a mixture of crushed iceand a saturated solution of CO'aN-az. The deposit is crushed in a mortarin the presence of a solution of CO3N2, it is iiltered, Washed with alittle water and dried in air. The dark product is crystallized inboiling water with discolouring charcoal. Yield: g. (34%) of bluish,mother-of-pearl flakes. M.P.=l52 153 C.

(g) 3-Chloro-Pyridazine--Carboxyamide (IX) 140 g. of ethyl3chloro-pyridazine--carboxylate are put in suspension in 560 cc. ofabsolute alcohol saturated by ammonia. A stream of NHSis passedtherethrough for 2 hours. The mixture is left over-night in `an ice box.It is filtered, washed with la little alcohol, and then with ether, anddried at 80 C Yield 115 g. (98%). M.P.=249 C.

(Iz) 3-HydrazinQ-Pyridazine-6-Carb0xamide (I) 105 g. of carboxamide areadded to a solution of 70 g.

of hydrazine hydrate in 1 litre of absolute alcohol. The mixture isrefluxedfor exactly 30 minutes It is cooled and then filtered. Theinsoluble part is boiled for l5 minutes with 800 cc. of water. Themixture is filtered while boiling, the insoluble 'part is Washed with'10() cc. of boiling water, v'and then put in contact with 200 cc. ofboiling Water for 5 minutes.V Yield: 58 g. (56%). M.P.=249-250 C. s

3-hydrazino-pyridazine-6-carboxamide gives with the acid salts `amongwhich may be mentioned for example hydrohalides, tartrates, maleates,.cina-tes, sulphates.

The scope of the invention is notrlimited to the modes of carrying outthe invention, which have been given merely by way of examples.

Having now described my invention what I claim as new and desire tosecure byY Letters Patent is:

A member selected from the group consisting of:3-hydrazino-pyridazine-carboxamide having the formula:

HZNO o-Q-NHNH 'and the therapeutically administrable acid 'additionsalts thereof. t Y .Y References Cited inthe le of this patent UNITEDSTATES PATENTS 2,484Q029 Hartmann et al. Oct. 11, 1949 FOREIGN PATENTS788,502 Great Britain Jan. 2, 195s OTHER REFERENCES Taylor et a1.:Organic Chemistry of Nitrogen (Revised 15 Edition, 1942), page 398.

Homer et' a1.: J. Chem. soc, London (1948), pp. 2191-9. y

